Annals ofthe Rheumatic Diseases 1992; 51: 1001-1004
1001
Recovery from pulmonary hypertension in an adolescent with mixed connective tissue disease Deborah M Friedman, Hal J Mitnick, Delores Danilowicz
in growth with vertebral fractures and aseptic necrosis of the femoral head. Azathioprine was later added for disease control. At 15 years of age an asymptomatic murmur was attributed to mitral valve prolapse, but no other abnormalities were seen by echocardiography. When she was 16 years old, one year after discontinuing azathioprine-treatment and decreasing the dose of steroids, an intercurrent respiratory infection indicated pulmonary hypertension, for which the steroid dose was increased. (Ann Rheum Dis 1992; 51: 1001-1004) Physical examination showed a small girl with Pulmonary hypertension is a serious and baffling an immature appearance and Cushingoid clinical problem, the optimum evaluation of features, weighing 34 kg and with a blood which still eludes definition and the treatment pressure of 105/85 mmHg. Her skin was taut of which is largely empirical. Secondary and dry and she had small tapered fingers and pulmonary hypertension may result from a toes. There was an area of chronic ischaemic variety of cardiac, pulmonary, or systemic changes on her right foot and ankle. There was diseases, or may present as an apparently no Homan's sign, no lymphadenopathy, and no primary disease with a predominantly arterio- hepatosplenomegaly. There was no jugular pathic, veno-occlusive or thromboembolic venous distension, clubbing, cyanosis or nature. Often life threatening in severity, the oedema. Her lungs were clear and pulses disease begins subtly in a poorly accessible strong. The right ventricular impulse was insite so that optimum diagnostic evaluation is creased; the second heart sound was palpable at delayed and difficult and treatment is still not the left upper sternal border and was loud and fully defined. This problem has now become single. There was an early systolic apical click and an intermittent grade 2/6 apical mid to late more widely recognised in children.' Mixed connective tissue disease is an auto- systolic 'whooping' murmur, but no diastolic immune disease rarely seen in children,2 but murmur. An electrocardiogram showed a right axis which is known to be associated with the development of pulmonary hypertension,35 deviation of + 120° and non-specific T wave which usually carries an unfavourable prognosis. changes, but no definite chamber hypertrophy. This paper describes an 11 year old girl with A chest radiograph showed a normal heart size mixed connective tissue disease who developed but a dilated main pulmonary artery shadow well documented pulmonary hypertension and and an enlarged right ventricle. The lung fields who responded to aggressive treatment with were clear. An echocardiogram showed a dilated right ventricle and pulmonary artery with apparent pulmonary vascular recovery. evidence of pulmonary hypertension by time intervals and pulmonary flow velocity timing (table 1). There was holosystolic mitral valve Case report An 11 year old Asian girl presented with mixed prolapse without regurgitation. connective tissue disease, including fever, Cardiac catheterisation (table 2) showed swollen hands, Raynaud's phenomenon, pleuro/ pulmonary hypertension at one third of systemic pericarditis, Coombs' positive anaemia, levels (aortic systolic pressure 115 mmHg, lymphadenitis and parotitis, circulating anti- pulmonary 37 mmHg) and a low cardiac index coagulant, restrictive lung disease, and inter- (2 I/min/m2), resulting in a pulmonary vascular mittent changes in urinary sediment. The resistance of 6 U/M2. The pulmonary artery representative serological profile early in her pressure increased with exercise. Trials with course included an antinuclear antibody titre of oxygen, isoprenaline hydrochloride, and hydra1/640 in a diffuse and speckled pattern, a lazine showed that the last drug was the most positive ribonucleoprotein (RNP) titre of efficacious and best tolerated vasodilator. Further evaluation at the time of catheter1/4x 106, an SM titre positive at 1/64, a latex fixation of 1/320, a negative titre for antibodies isation showed a haemoglobin concentration of to double stranded DNA, a normal initial C3, 91 g/l, an erythrocyte sedimentation rate of but C4 markedly reduced at 75 mg/I. She was 120-140 mm/hour, white blood cell count treated with salicylates and steroids, which 4-10x 109/l, and platelet count 101 x 109/1. The resulted in clinical improvement despite a delay protime was normal, but the partial thrombo-
Abstract This paper describes the case of an 11 year old girl who presented with mixed connective tissue disease which was complicated by the development of pulmonary hypertension. This case is unique with respect to the young age of onset, the serial non-invasive method used to follow the disease process, and the favourable response to treatment with vasodilator and anti-inflammatory drugs.
Division of Pediatric Cardiology,
New York University Medical Center, New York, NY, USA D M Friedman D Danilowicz Division of
Rheumatology, New York University Medical Center, New York, NY, USA H J Mitnick Correspondence to: Dr Deborah M Friedman, Division of Pediatric Cardiology, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA. Accepted for publication 15 October 1991
Friedman, Mitnick, Danilowicz
1002
Table I Clinical data March 1984
Measured parameter Right systolic time interval Pulmonary artery acceleration time (ms) Erythrocyte sedimentation rate (mm/hour) Haemoglobin (g/l) Weight (kg) Platelets (x109/1) C3 (mg/l) C4 (mg/l) RNP
Treannent: Prednisone qod$ S mg
May 1984*
July 1984
August 1984 0*40
October
1984t
January 1985
-
0-44
80
80
80
128
-
85
130 99 34 137
25 133 40
% 41-5 100
62 114 43-5 168
-
-
1 35 qod
0 34
0-44
0 44
-
100 43 5 -
-
-
-
13 1/40 960
-
-
-
T 1S qd$
T20 tid$
140 qod
24
July
March 1985
1985
0 40
0-38
100
130
52
95 177
40 104 43-5 198
-
-
-
-
-
-
-
-
1 20 qod
-
-
42-3 168
112-5 qod
Begin 25 mg
Hydralazine
qidt
Begin
Cyclophosphamide
37 5 mg qd
Stop for Restart low white 25 qd blood cell count
-
*Date of first catheterisation. tDate of second catheterisation. *qod=every other day; qd=every day; tid=three times a day; bid=twice a day; qid=four times a day.
Table 2 Catheterisation data 9 October 1984
10 May 1984
Heart rate (beats/min) Aortic pressure (mmHg) Aortic saturation (%) Aortic Po2 (mmHg) Pulmonary pressure (mmHg) Pulmonary saturation (%) Pulmonary Po2 (mmHg) Mean right atrial pressure (mmHg) Mean pulmonary capillary pressure (mmHg) Oxygen consumption (ml/min/m2) Arteriovenous oxygen difference (ml/dl) Cardiac output (1/min) Pulmonary vascular resistance (U/m2) Systemic vascular resistance (U/M2) PVR/SVR Right systolic time interval (M mode) Doppler acceleration time (ms)
Rest
100%1* oxygen
Isoprenaline
70
74
94
99 430
97 95 45/25, 35
115/75, 95
96 89
37/10, 20 60 32 3 5 124 4-5 2-4 6 38 0-2 0-23 80
Hydralazine
Exercise
120 110/88, 102 96 -
40 3
63 36 8
94 95/70, 82 97 96 35/12, 24 68 35 3
4
5 206
6 181
-
105/75, 88
42/20, 30 70
-
4-5 -
-
105/68, 75
4-4 4-7 6 14 0-4 0-38 -
Rest without
Hydralazine
drugs
hydrochloride*
3.9
4-7 3/8 17 0-2 0-29 80
48/30, 40 75 -
2-8 -
85 125/85, 100 98 98 50/28, 34 69 45 3
115 100/72, 85 98 95 45/25, 34 75 50 3
7 145
5 128
4-1 4.9 55 20 03 0 40 128
3-2 5.4 4-9 16 03 -
*Patient developed nausea, hypertension, and bradycardia.
plastin time was increased 43-9 s (control 32 s), and a circulating anticoagulant was shown. A single urine sample revealed 4+ proteinuria with 5-10 red blood cells and white blood cells per high power field. Subsequent urine analysis, however, was normal and nephritis was not seen. Pulmonary function tests showed a moderate restrictive abnormality with normal diffusion, and gallium and ventilation/perfusion lung scans, and peripheral venous Doppler examination ruled out pulmonary emboli and deep vein thrombosis. A lung biopsy sample was not taken. Nailfold capillary microscopy showed dilatory changes of the scleroderma type. Serologies remained positive as before, with a low C4 and a positive titre for antiSSA (Ro). In the presence ofpulmonary hypertension and active serologies, she was treated again with high dose prednisone, hydralazine was begun at 25 mg four times a day by mouth, and cyclophosphamide was added for further immuno-
suppression.
Over the next four months she showed subjective and objective improvement on this drug regimen. The Doppler pulmonary artery acceleration time was still prolonged, but the M mode right sided systolic time intervals decreased. Her sedimentation rate decreased from 120 to 25 mm/hour, and the steroid dose was tapered. A repeat cardiac catheterisation five months after the first (table 2) showed persistent pulmonary hypertension (aortic systolic pressure 125 mmHg, pulmonary 50 mmHg) with a stable pulmonary vascular resistance of 5 5 U/M2. Acute drug testing showed persistent responsiveness to hydralazine with an increase in the cardiac index from 3 5 to 3-9 1/min/M2. Therefore the regimen of corticosteroids, cyclophosphamide, and hydralazine was continued, in tapering doses, over the next four years. The course was complicated only by transient neutropenia and thrombocytopenia, associated with antibodies to platelets.
Pulmonary hypertenson in mixed connective tissue disease
October 1985
February 1986
0-28
0-29
May 1986
June 1986
-
-
July
1986 0 30
1003
April 1987
March 1988
Mav 1988
Mav 1989
-
-
-
-
140
140
-
-
120
-
-
110
-
70 115 42-7 140
53 115 44 134
60 120 -
42 5 -
-
-
-
-
-
46 128 380 73 22
-
-
0
46 79 9 1/1280
73 62 29 17 1/10,240
69 130 43 43 23 -
111 34 19 1/2560
75 qod
qod
45
-
-
T40
-
25 qd
-
-
-
-
-
qd 25
-
bidt Discontinued
Within three years of the recognition of pulmonary hypertension, the patient was completely asymptomatic. Her cardiac examination returned entirely to normal, and her electrocardiogram became normal with an axis of +80°. The echocardiogram was normal without mitral valve prolapse, the pulmonary acceleration time was 110 ms, and the right systolic time interval was 0 30. Her haemoglobin increased to 130 g/l, and her weight to 43 kg, but the sedimentation rate remained at 45 mm/hour and the platelet count 118 x 109/l. She currently receives only a maintenance dose of steroids for autoimmune thrombocytopenia and has no evidence of pulmonary hypertension. When first measured at the age of 20 years, her anticardiolipin antibody titre was borderline for IgG and negative in other subclasses; the titres were all negative at 21 years of age. Methods Cardiac catheterisation was performed using the Fick method with measured oxygen consumption. A pulmonary vascular resistance greater than 3 U/m2 was considered abnormal, as was a systolic pulmonary artery pressure greater than 35 mmHg (mean 22). Echocardiography was performed with a duplex pulsed Doppler unit using a 3 0 mHz transducer. From a cross sectional parasternal view, the cursor was placed along the axis of the main pulmonary artery with the Doppler sample volume just distal to the valve leaflets. An M mode tracing of the pulmonary valve allowed direct measurement of the pre-ejection period (onset of QRS to valve opening) and systolic ejection time (valve opening to closure) and a ratio greater than 0 30 was considered abnormal. From the pulmonary artery Doppler flow waveforms, the acceleration time was taken as the interval from onset to the peak velocity of flow. An acceleration time of less than 100 ms was considered abnormal; 100 to 120 ms was borderline, and an acceleration time over 120 was considered normal.6 7
Discussion Mixed connective tissue disease is an overlap syndrome of autoimmune disease with features resembling systemic lupus erythematosus, scleroderma, and dermatomyositis, but with a characteristic serological picture.2 Our patient showed various findings over a period of time, but her disease never evolved clearly into any of the other collagen vascular disease categories. Although some may argue that the intermittently positive titre for antiSm favours a diagnosis of lupus erythematosus, we felt her overall pattern best fitted the diagnosis of mixed connective tissue disease. This disease has a known tendency towards the development of pulmonary hypertension.3"5 The pathophysiology is not fully known, but may be similar to that in primary pulmonary hypertension, a disease in which there is a high incidence of positive serologies for collagen vascular disease.8 Limited pathological studies in mixed connective tissue disease3 have shown features which are characteristic of pulmonary hypertension in general, including right ventricular hypertrophy, marked intimal proliferation, and medial hypertrophy of pulmonary arteries and arterioles. The part played by in situ thrombosis, as shown in pulmonary hypertension,9 10 has not been well defined in mixed connective tissue disease.5 This suggests, however, a possible role for the lupus anticoagulant,"I such as in our patient, in the origin or progression of this process. Although anticardiolipin antibodies may theoretically affect thrombosis, we were unable to measure them in our patient until 1988, when they were normal. Several additional clinical features deserve comment. During aggressive treatment, the cardiopulmonary improvement seemed to parallel the improved serological data and resolution of thrombocytopenia. Despite later serological and haematological relapses, which occurred as the drugs were tapered to less toxic levels, the pulmonary vascular remission was maintained. Secondly, dilated nailfold capillary microscopy changes of the scleroderma type were seen in this patient. These findings are associated with pulmonary hypertension in mixed connective tissue disease.3 Finally, the patient had a well documented mitral valve prolapse, which disappeared as the disease came under control. This finding underlines the observed association between mitral valve prolapse and collagen vascular disease.'2 Clinical evaluation of patients with pulmonary hypertension has generally required the use of serial invasive cardiac catheterisations to measure pulmonary artery pressure and flow. This is clearly not ideal for a sick child owing to its morbidity, discomfort, and cost. Improvements in the technology of ultrasound have provided a non-invasive serially applicable means of assessing the pulmonary pressure. The use of two dimensional echocardiography has shown the predictive value of flattening and posterior displacement of the interventricular septum toward the lumen of the left ventricle, indicating right ventricular hypertension.'3 '" This finding is seen only with the more severe
Friedman, Mitnick, Danilbicz
1004
disease, however, and is difficult to quantitate. Although right sided systolic time intervals measured by M mode echocardiography to assess pulmonary pressures are non-invasive, they are not accurate. When combined with Doppler derived time intervals of pulmonary flow velocity, such as the accleration time, however, the predictive accuracy is improved, and a useful non-invasive assessment tool for pulmonary hypertension is available.6 7 These methods were used in this patient, and allowed less frequent invasive catheterisations to measure pulmonary pressure and resistance. This case is unique in that a new non-invasive technology was the key to diagnosis and serial evaluation of pulmonary hypertension in mixed connective tissue disease. Treatment for pulmonary hypertension is empirical and usually unsuccessful. The underlying disease, if present, is treated, and in this instance included the vigorous use of steroids and antimetabolites. If thromboembolism is felt to play a part, then anticoagulants may be used.9 '° Attention has recently focused on the use of vasodilator drugs for short term clinical benefit, and perhaps for long term reversal of the underlying process. Classes of drugs include the direct vasodilators such as hydralazine,'5 16 calcium channel blockers such as nifedipine,17 and prostaglandins such as prostacyclin. 8 These drugs have had variable results. The patient in this study was treated with hydralazine, which during acute invasive drug testing was effective and was the better tolerated drug. The prognosis of pulmonary hypertension is generally poor in most natural history studies,3 and not much improved even with the use of long term vasodilatation.'9 Therefore, this patient is unusual in that, with aggressive vasodilatation and treatment of the underlying disease, subjective and objective evidence of recovery from pulmonary hypertension was achieved. Perkin R M, Anas N G. patients.
J7
Pulmonary hypertension
Pediatr 1984; 105: 511-22.
in
pediatric
2 Singsen B H, Bernstein B H, Kornreich H K, King K K, Hanson V, Tan E M. Mixed connective tissue disease in childhood. A clinical and serologic survey. J Pediatr 1977; 90: 893-900. 3 Sullivan W D, Hurst D J, Harmon C E, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore) 1984; 63: 92-107. 4 Singsen B H, Platzker A C G. Pulmonary involvement in the rheumatic disorders of childhood. In: Kendig E L, Jr., Chernick V, eds. Disorders of the respiratory tract in children. 4th ed. Philadelphia: Saunders, 1983: 863-5. 5 Jones M B, Osterholm R K, Wilson R B, Martin F H, Commers J R, Bachmayer J 0. Fatal pulmonary hypertension and resolving immune-complex glomerulonephritis in mixed connective tissue disease. Am 7 Med 1978; 65: 855-63. 6 Kitabatake A, Inoue M, Asao M, et al. Noninvasive evaluation of pulmonary hypertension by a pulsed Doppler technique. Circulation 1983; 68: 302-9. 7 Kosturakis D, Goldberg S J, Allen H D, Loeber C. Doppler echocardiographic prediction of pulmonary arterial hypertension in congenital heart disease. AmJ Cardiol 1984; 53: 1110-5. 8 Rich S, Kieras K, Hart K, Groves B M, Stobo J D, Brundage B H. Antinuclear antibodies in primary pulmonary hypertension. J7 Am Coll Cardiol 1986; 8: 1307-11. 9 Fuster V, Steele P M, Edwards W D, Gersh B J, McGoon M D, Frye R L. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70: 580-7. 10 Cohen M, Edwards W D, Fuster V. Regression in thromboembolic type of primary pulmonary hypertension during 21/2 years of antithrombotic therapy. Jf Am Coll Cardiol 1986; 7: 172-5. 11 Asherton A, Mackworth-Young G, Boey L, Hull G, Saunders S, Gharavi E, Hughes G R V. Pulmonary hypertension in systemic lupus erythematosus. BMJ 1983; 287: 1024-5. 12 Comens S M, Alpert M A, Sharp G C, et al. Frequency of mitral valve prolapse in systemic lupus erythematosus, progressive systemic sclerosis and mixed connective tissue disease. Am J Cardiol 1989; 63: 369-70. 13 King M E, Braun H, Goldblatt A, Liberthson R, Weyman A E. Interventricular septal configuration as a predictor of right ventricular systolic hypertension in children: a crosssectional echocardiographic study. Circulation 1983; 68: 68-75. 14 Ryan T, Petrovic 0, Dillon J C, Feigenbaum H, Conley M J, Armstrong W F. An echocardiopgraphic index for separation of right ventricular volume and pressure overload. J Am Coll Cardiol 1985; 5: 918-24. 15 Rubin L J, Peter R H. Oral hydralazine therapy for primary pulmonary hypertension. N EnglJ Med 1980; 302: 69-73. 16 Packer M, Medina N, Yushak M. Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease. J Am CoU Cardiol 1984; 4: 890-901. 17 Rich S, Brundage B H. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary artery pressure and regression of right ventricular hypertrophy. Circulation 1987; 76: 13541. 18 Bush A, Busst C, Booth K, Knight W B, Shinebourne E A. Does prostacyclin enhance the selective pulmonary vasodilator effect of oxygen in children with congenital heart disease? Circulation 1986; 74: 135-44. 19 Rich S, Brundage B H, Levy P S. The effect of vasodilator therapy on the clinical outcome of patients with primary pulmonary hypertension. Circulation 1985; 71: 1191-6.
1001
Recovery from pulmonary hypertension in an adolescent with mixed connective tissue disease Deborah M Friedman, Hal J Mitnick, Delores Danilowicz
in growth with vertebral fractures and aseptic necrosis of the femoral head. Azathioprine was later added for disease control. At 15 years of age an asymptomatic murmur was attributed to mitral valve prolapse, but no other abnormalities were seen by echocardiography. When she was 16 years old, one year after discontinuing azathioprine-treatment and decreasing the dose of steroids, an intercurrent respiratory infection indicated pulmonary hypertension, for which the steroid dose was increased. (Ann Rheum Dis 1992; 51: 1001-1004) Physical examination showed a small girl with Pulmonary hypertension is a serious and baffling an immature appearance and Cushingoid clinical problem, the optimum evaluation of features, weighing 34 kg and with a blood which still eludes definition and the treatment pressure of 105/85 mmHg. Her skin was taut of which is largely empirical. Secondary and dry and she had small tapered fingers and pulmonary hypertension may result from a toes. There was an area of chronic ischaemic variety of cardiac, pulmonary, or systemic changes on her right foot and ankle. There was diseases, or may present as an apparently no Homan's sign, no lymphadenopathy, and no primary disease with a predominantly arterio- hepatosplenomegaly. There was no jugular pathic, veno-occlusive or thromboembolic venous distension, clubbing, cyanosis or nature. Often life threatening in severity, the oedema. Her lungs were clear and pulses disease begins subtly in a poorly accessible strong. The right ventricular impulse was insite so that optimum diagnostic evaluation is creased; the second heart sound was palpable at delayed and difficult and treatment is still not the left upper sternal border and was loud and fully defined. This problem has now become single. There was an early systolic apical click and an intermittent grade 2/6 apical mid to late more widely recognised in children.' Mixed connective tissue disease is an auto- systolic 'whooping' murmur, but no diastolic immune disease rarely seen in children,2 but murmur. An electrocardiogram showed a right axis which is known to be associated with the development of pulmonary hypertension,35 deviation of + 120° and non-specific T wave which usually carries an unfavourable prognosis. changes, but no definite chamber hypertrophy. This paper describes an 11 year old girl with A chest radiograph showed a normal heart size mixed connective tissue disease who developed but a dilated main pulmonary artery shadow well documented pulmonary hypertension and and an enlarged right ventricle. The lung fields who responded to aggressive treatment with were clear. An echocardiogram showed a dilated right ventricle and pulmonary artery with apparent pulmonary vascular recovery. evidence of pulmonary hypertension by time intervals and pulmonary flow velocity timing (table 1). There was holosystolic mitral valve Case report An 11 year old Asian girl presented with mixed prolapse without regurgitation. connective tissue disease, including fever, Cardiac catheterisation (table 2) showed swollen hands, Raynaud's phenomenon, pleuro/ pulmonary hypertension at one third of systemic pericarditis, Coombs' positive anaemia, levels (aortic systolic pressure 115 mmHg, lymphadenitis and parotitis, circulating anti- pulmonary 37 mmHg) and a low cardiac index coagulant, restrictive lung disease, and inter- (2 I/min/m2), resulting in a pulmonary vascular mittent changes in urinary sediment. The resistance of 6 U/M2. The pulmonary artery representative serological profile early in her pressure increased with exercise. Trials with course included an antinuclear antibody titre of oxygen, isoprenaline hydrochloride, and hydra1/640 in a diffuse and speckled pattern, a lazine showed that the last drug was the most positive ribonucleoprotein (RNP) titre of efficacious and best tolerated vasodilator. Further evaluation at the time of catheter1/4x 106, an SM titre positive at 1/64, a latex fixation of 1/320, a negative titre for antibodies isation showed a haemoglobin concentration of to double stranded DNA, a normal initial C3, 91 g/l, an erythrocyte sedimentation rate of but C4 markedly reduced at 75 mg/I. She was 120-140 mm/hour, white blood cell count treated with salicylates and steroids, which 4-10x 109/l, and platelet count 101 x 109/1. The resulted in clinical improvement despite a delay protime was normal, but the partial thrombo-
Abstract This paper describes the case of an 11 year old girl who presented with mixed connective tissue disease which was complicated by the development of pulmonary hypertension. This case is unique with respect to the young age of onset, the serial non-invasive method used to follow the disease process, and the favourable response to treatment with vasodilator and anti-inflammatory drugs.
Division of Pediatric Cardiology,
New York University Medical Center, New York, NY, USA D M Friedman D Danilowicz Division of
Rheumatology, New York University Medical Center, New York, NY, USA H J Mitnick Correspondence to: Dr Deborah M Friedman, Division of Pediatric Cardiology, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA. Accepted for publication 15 October 1991
Friedman, Mitnick, Danilowicz
1002
Table I Clinical data March 1984
Measured parameter Right systolic time interval Pulmonary artery acceleration time (ms) Erythrocyte sedimentation rate (mm/hour) Haemoglobin (g/l) Weight (kg) Platelets (x109/1) C3 (mg/l) C4 (mg/l) RNP
Treannent: Prednisone qod$ S mg
May 1984*
July 1984
August 1984 0*40
October
1984t
January 1985
-
0-44
80
80
80
128
-
85
130 99 34 137
25 133 40
% 41-5 100
62 114 43-5 168
-
-
1 35 qod
0 34
0-44
0 44
-
100 43 5 -
-
-
-
13 1/40 960
-
-
-
T 1S qd$
T20 tid$
140 qod
24
July
March 1985
1985
0 40
0-38
100
130
52
95 177
40 104 43-5 198
-
-
-
-
-
-
-
-
1 20 qod
-
-
42-3 168
112-5 qod
Begin 25 mg
Hydralazine
qidt
Begin
Cyclophosphamide
37 5 mg qd
Stop for Restart low white 25 qd blood cell count
-
*Date of first catheterisation. tDate of second catheterisation. *qod=every other day; qd=every day; tid=three times a day; bid=twice a day; qid=four times a day.
Table 2 Catheterisation data 9 October 1984
10 May 1984
Heart rate (beats/min) Aortic pressure (mmHg) Aortic saturation (%) Aortic Po2 (mmHg) Pulmonary pressure (mmHg) Pulmonary saturation (%) Pulmonary Po2 (mmHg) Mean right atrial pressure (mmHg) Mean pulmonary capillary pressure (mmHg) Oxygen consumption (ml/min/m2) Arteriovenous oxygen difference (ml/dl) Cardiac output (1/min) Pulmonary vascular resistance (U/m2) Systemic vascular resistance (U/M2) PVR/SVR Right systolic time interval (M mode) Doppler acceleration time (ms)
Rest
100%1* oxygen
Isoprenaline
70
74
94
99 430
97 95 45/25, 35
115/75, 95
96 89
37/10, 20 60 32 3 5 124 4-5 2-4 6 38 0-2 0-23 80
Hydralazine
Exercise
120 110/88, 102 96 -
40 3
63 36 8
94 95/70, 82 97 96 35/12, 24 68 35 3
4
5 206
6 181
-
105/75, 88
42/20, 30 70
-
4-5 -
-
105/68, 75
4-4 4-7 6 14 0-4 0-38 -
Rest without
Hydralazine
drugs
hydrochloride*
3.9
4-7 3/8 17 0-2 0-29 80
48/30, 40 75 -
2-8 -
85 125/85, 100 98 98 50/28, 34 69 45 3
115 100/72, 85 98 95 45/25, 34 75 50 3
7 145
5 128
4-1 4.9 55 20 03 0 40 128
3-2 5.4 4-9 16 03 -
*Patient developed nausea, hypertension, and bradycardia.
plastin time was increased 43-9 s (control 32 s), and a circulating anticoagulant was shown. A single urine sample revealed 4+ proteinuria with 5-10 red blood cells and white blood cells per high power field. Subsequent urine analysis, however, was normal and nephritis was not seen. Pulmonary function tests showed a moderate restrictive abnormality with normal diffusion, and gallium and ventilation/perfusion lung scans, and peripheral venous Doppler examination ruled out pulmonary emboli and deep vein thrombosis. A lung biopsy sample was not taken. Nailfold capillary microscopy showed dilatory changes of the scleroderma type. Serologies remained positive as before, with a low C4 and a positive titre for antiSSA (Ro). In the presence ofpulmonary hypertension and active serologies, she was treated again with high dose prednisone, hydralazine was begun at 25 mg four times a day by mouth, and cyclophosphamide was added for further immuno-
suppression.
Over the next four months she showed subjective and objective improvement on this drug regimen. The Doppler pulmonary artery acceleration time was still prolonged, but the M mode right sided systolic time intervals decreased. Her sedimentation rate decreased from 120 to 25 mm/hour, and the steroid dose was tapered. A repeat cardiac catheterisation five months after the first (table 2) showed persistent pulmonary hypertension (aortic systolic pressure 125 mmHg, pulmonary 50 mmHg) with a stable pulmonary vascular resistance of 5 5 U/M2. Acute drug testing showed persistent responsiveness to hydralazine with an increase in the cardiac index from 3 5 to 3-9 1/min/M2. Therefore the regimen of corticosteroids, cyclophosphamide, and hydralazine was continued, in tapering doses, over the next four years. The course was complicated only by transient neutropenia and thrombocytopenia, associated with antibodies to platelets.
Pulmonary hypertenson in mixed connective tissue disease
October 1985
February 1986
0-28
0-29
May 1986
June 1986
-
-
July
1986 0 30
1003
April 1987
March 1988
Mav 1988
Mav 1989
-
-
-
-
140
140
-
-
120
-
-
110
-
70 115 42-7 140
53 115 44 134
60 120 -
42 5 -
-
-
-
-
-
46 128 380 73 22
-
-
0
46 79 9 1/1280
73 62 29 17 1/10,240
69 130 43 43 23 -
111 34 19 1/2560
75 qod
qod
45
-
-
T40
-
25 qd
-
-
-
-
-
qd 25
-
bidt Discontinued
Within three years of the recognition of pulmonary hypertension, the patient was completely asymptomatic. Her cardiac examination returned entirely to normal, and her electrocardiogram became normal with an axis of +80°. The echocardiogram was normal without mitral valve prolapse, the pulmonary acceleration time was 110 ms, and the right systolic time interval was 0 30. Her haemoglobin increased to 130 g/l, and her weight to 43 kg, but the sedimentation rate remained at 45 mm/hour and the platelet count 118 x 109/l. She currently receives only a maintenance dose of steroids for autoimmune thrombocytopenia and has no evidence of pulmonary hypertension. When first measured at the age of 20 years, her anticardiolipin antibody titre was borderline for IgG and negative in other subclasses; the titres were all negative at 21 years of age. Methods Cardiac catheterisation was performed using the Fick method with measured oxygen consumption. A pulmonary vascular resistance greater than 3 U/m2 was considered abnormal, as was a systolic pulmonary artery pressure greater than 35 mmHg (mean 22). Echocardiography was performed with a duplex pulsed Doppler unit using a 3 0 mHz transducer. From a cross sectional parasternal view, the cursor was placed along the axis of the main pulmonary artery with the Doppler sample volume just distal to the valve leaflets. An M mode tracing of the pulmonary valve allowed direct measurement of the pre-ejection period (onset of QRS to valve opening) and systolic ejection time (valve opening to closure) and a ratio greater than 0 30 was considered abnormal. From the pulmonary artery Doppler flow waveforms, the acceleration time was taken as the interval from onset to the peak velocity of flow. An acceleration time of less than 100 ms was considered abnormal; 100 to 120 ms was borderline, and an acceleration time over 120 was considered normal.6 7
Discussion Mixed connective tissue disease is an overlap syndrome of autoimmune disease with features resembling systemic lupus erythematosus, scleroderma, and dermatomyositis, but with a characteristic serological picture.2 Our patient showed various findings over a period of time, but her disease never evolved clearly into any of the other collagen vascular disease categories. Although some may argue that the intermittently positive titre for antiSm favours a diagnosis of lupus erythematosus, we felt her overall pattern best fitted the diagnosis of mixed connective tissue disease. This disease has a known tendency towards the development of pulmonary hypertension.3"5 The pathophysiology is not fully known, but may be similar to that in primary pulmonary hypertension, a disease in which there is a high incidence of positive serologies for collagen vascular disease.8 Limited pathological studies in mixed connective tissue disease3 have shown features which are characteristic of pulmonary hypertension in general, including right ventricular hypertrophy, marked intimal proliferation, and medial hypertrophy of pulmonary arteries and arterioles. The part played by in situ thrombosis, as shown in pulmonary hypertension,9 10 has not been well defined in mixed connective tissue disease.5 This suggests, however, a possible role for the lupus anticoagulant,"I such as in our patient, in the origin or progression of this process. Although anticardiolipin antibodies may theoretically affect thrombosis, we were unable to measure them in our patient until 1988, when they were normal. Several additional clinical features deserve comment. During aggressive treatment, the cardiopulmonary improvement seemed to parallel the improved serological data and resolution of thrombocytopenia. Despite later serological and haematological relapses, which occurred as the drugs were tapered to less toxic levels, the pulmonary vascular remission was maintained. Secondly, dilated nailfold capillary microscopy changes of the scleroderma type were seen in this patient. These findings are associated with pulmonary hypertension in mixed connective tissue disease.3 Finally, the patient had a well documented mitral valve prolapse, which disappeared as the disease came under control. This finding underlines the observed association between mitral valve prolapse and collagen vascular disease.'2 Clinical evaluation of patients with pulmonary hypertension has generally required the use of serial invasive cardiac catheterisations to measure pulmonary artery pressure and flow. This is clearly not ideal for a sick child owing to its morbidity, discomfort, and cost. Improvements in the technology of ultrasound have provided a non-invasive serially applicable means of assessing the pulmonary pressure. The use of two dimensional echocardiography has shown the predictive value of flattening and posterior displacement of the interventricular septum toward the lumen of the left ventricle, indicating right ventricular hypertension.'3 '" This finding is seen only with the more severe
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disease, however, and is difficult to quantitate. Although right sided systolic time intervals measured by M mode echocardiography to assess pulmonary pressures are non-invasive, they are not accurate. When combined with Doppler derived time intervals of pulmonary flow velocity, such as the accleration time, however, the predictive accuracy is improved, and a useful non-invasive assessment tool for pulmonary hypertension is available.6 7 These methods were used in this patient, and allowed less frequent invasive catheterisations to measure pulmonary pressure and resistance. This case is unique in that a new non-invasive technology was the key to diagnosis and serial evaluation of pulmonary hypertension in mixed connective tissue disease. Treatment for pulmonary hypertension is empirical and usually unsuccessful. The underlying disease, if present, is treated, and in this instance included the vigorous use of steroids and antimetabolites. If thromboembolism is felt to play a part, then anticoagulants may be used.9 '° Attention has recently focused on the use of vasodilator drugs for short term clinical benefit, and perhaps for long term reversal of the underlying process. Classes of drugs include the direct vasodilators such as hydralazine,'5 16 calcium channel blockers such as nifedipine,17 and prostaglandins such as prostacyclin. 8 These drugs have had variable results. The patient in this study was treated with hydralazine, which during acute invasive drug testing was effective and was the better tolerated drug. The prognosis of pulmonary hypertension is generally poor in most natural history studies,3 and not much improved even with the use of long term vasodilatation.'9 Therefore, this patient is unusual in that, with aggressive vasodilatation and treatment of the underlying disease, subjective and objective evidence of recovery from pulmonary hypertension was achieved. Perkin R M, Anas N G. patients.
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2 Singsen B H, Bernstein B H, Kornreich H K, King K K, Hanson V, Tan E M. Mixed connective tissue disease in childhood. A clinical and serologic survey. J Pediatr 1977; 90: 893-900. 3 Sullivan W D, Hurst D J, Harmon C E, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore) 1984; 63: 92-107. 4 Singsen B H, Platzker A C G. Pulmonary involvement in the rheumatic disorders of childhood. In: Kendig E L, Jr., Chernick V, eds. Disorders of the respiratory tract in children. 4th ed. Philadelphia: Saunders, 1983: 863-5. 5 Jones M B, Osterholm R K, Wilson R B, Martin F H, Commers J R, Bachmayer J 0. Fatal pulmonary hypertension and resolving immune-complex glomerulonephritis in mixed connective tissue disease. Am 7 Med 1978; 65: 855-63. 6 Kitabatake A, Inoue M, Asao M, et al. Noninvasive evaluation of pulmonary hypertension by a pulsed Doppler technique. Circulation 1983; 68: 302-9. 7 Kosturakis D, Goldberg S J, Allen H D, Loeber C. Doppler echocardiographic prediction of pulmonary arterial hypertension in congenital heart disease. AmJ Cardiol 1984; 53: 1110-5. 8 Rich S, Kieras K, Hart K, Groves B M, Stobo J D, Brundage B H. Antinuclear antibodies in primary pulmonary hypertension. J7 Am Coll Cardiol 1986; 8: 1307-11. 9 Fuster V, Steele P M, Edwards W D, Gersh B J, McGoon M D, Frye R L. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70: 580-7. 10 Cohen M, Edwards W D, Fuster V. Regression in thromboembolic type of primary pulmonary hypertension during 21/2 years of antithrombotic therapy. Jf Am Coll Cardiol 1986; 7: 172-5. 11 Asherton A, Mackworth-Young G, Boey L, Hull G, Saunders S, Gharavi E, Hughes G R V. Pulmonary hypertension in systemic lupus erythematosus. BMJ 1983; 287: 1024-5. 12 Comens S M, Alpert M A, Sharp G C, et al. Frequency of mitral valve prolapse in systemic lupus erythematosus, progressive systemic sclerosis and mixed connective tissue disease. Am J Cardiol 1989; 63: 369-70. 13 King M E, Braun H, Goldblatt A, Liberthson R, Weyman A E. Interventricular septal configuration as a predictor of right ventricular systolic hypertension in children: a crosssectional echocardiographic study. Circulation 1983; 68: 68-75. 14 Ryan T, Petrovic 0, Dillon J C, Feigenbaum H, Conley M J, Armstrong W F. An echocardiopgraphic index for separation of right ventricular volume and pressure overload. J Am Coll Cardiol 1985; 5: 918-24. 15 Rubin L J, Peter R H. Oral hydralazine therapy for primary pulmonary hypertension. N EnglJ Med 1980; 302: 69-73. 16 Packer M, Medina N, Yushak M. Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease. J Am CoU Cardiol 1984; 4: 890-901. 17 Rich S, Brundage B H. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary artery pressure and regression of right ventricular hypertrophy. Circulation 1987; 76: 13541. 18 Bush A, Busst C, Booth K, Knight W B, Shinebourne E A. Does prostacyclin enhance the selective pulmonary vasodilator effect of oxygen in children with congenital heart disease? Circulation 1986; 74: 135-44. 19 Rich S, Brundage B H, Levy P S. The effect of vasodilator therapy on the clinical outcome of patients with primary pulmonary hypertension. Circulation 1985; 71: 1191-6.
